Bouras Toula, Pal Bhupinder, Vaillant François, Harburg Gwyndolen, Asselin-Labat Marie-Liesse, Oakes Samantha R, Lindeman Geoffrey J, Visvader Jane E
VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Cell Stem Cell. 2008 Oct 9;3(4):429-41. doi: 10.1016/j.stem.2008.08.001.
The recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage. Notably, constitutive Notch signaling specifically targeted luminal progenitor cells for expansion, leading to hyperplasia and tumorigenesis. These findings reveal key roles for Notch signaling in MaSCs and luminal cell commitment and further suggest that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.
近期对小鼠乳腺干细胞（MaSCs）及其祖细胞亚群的鉴定，增强了研究其谱系定向分化遗传控制的前景。在此，我们探究了Notch信号通路在乳腺上皮层级结构中的作用。我们发现，在富含MaSC的群体中敲低经典Notch效应因子Cbf-1，会导致体内干细胞活性增加以及异常终末芽的形成，这意味着内源性Notch信号在限制MaSC扩增中发挥作用。相反，在体内导管腔上皮中发现Notch被优先激活，且专门促进MaSC沿腔谱系的定向分化。值得注意的是，组成型Notch信号特异性靶向腔祖细胞进行扩增，导致增生和肿瘤发生。这些发现揭示了Notch信号在MaSC和腔细胞定向分化中的关键作用，并进一步表明Notch的不适当激活促进了腔祖细胞的自我更新和转化。
